Immune responses are of two general types: innate and adaptive. Generally, innate immune responses are fast and rapid, whereas adaptive immune responses are slower to be induced but subsequently provide immunological memory. Innate responses can trigger inflammation, for example because the cells of innate immunity produce hormone-like (‘pro-inflammatory’) cytokines such as interleukins (IL-1, IL-6) and tumour necrosis factor (TNF)-alpha. Crucially, innate immune responses are also usually required for the initiation and regulation of adaptive responses.
Innate immune responses can be mediated by cells such as monocytes and macrophages, mast cells, and granulocytes including neutrophils, eosinophils and basophils and NK cells. Innate-like immune responses may also be mediated by cells such as NKT cells, including invariant NKT cells, and gamma-delta T cells.
Dendritic cells (DCs) are specialised cells of immunity that provide an important link between innate and adaptive immune responses. They express a diversity of molecular sensors that enable them to detect and discriminate between different types of ‘danger’, such as viral or microbial infections, and perhaps cellular damage, whether or not it is caused by an infection. DCs subsequently change their properties in response to the ‘danger’ (for example they may secrete the cytokine IL-12 and up-regulate expression of co-stimulatory molecules such as CD86, in a process often termed ‘activation’ or ‘maturation’). This enables them to initiate and regulate adaptive immune responses that are typically mediated by lymphocytes.
Adaptive immune responses include specific antibody responses that may, for example, help to clear infectious agents, and cytotoxic T cell responses that may enable killing of infected cells and tumour cells. Antibodies are produced by B lymphocytes (as plasma cells) whereas cytotoxic T cells generally develop from the CD8+ T cell subset (and, perhaps less frequently, from the CD4+ T cell subset).
Immunological interventions can be used, in theory or in practice, to modulate immune responses. Vaccines typically stimulate immune responses against, for example, infectious diseases or cancers. In contrast, other approaches, experimentally or clinically, may suppress aberrant or unwanted immune responses. These include allergies and other immune-related sensitivities (sometimes termed ‘hypersensitivity diseases’), autoimmune diseases, and transplantation reactions (including transplant rejection and graft-versus-host disease). Any agent that acts to modulate an immune response, whether by stimulating or suppressing a response, may be termed an immune modulator.
An immunogenic composition is a composition that can be used to modulate immune responses. Such a composition generally comprises an antigen (a substance against which an adaptive immune response may be directed; this response may involve antibodies or cytotoxic T cells, or both) and an immune modulator.
DNA vaccination is known and therefore an antigen may be a macromolecule, such as a polypeptide chain, an RNA preparation that can be translated into a polypeptide chain, or a DNA preparation that encodes a polypeptide chain and that may be transcribed into an RNA intermediate. The antigen may be a DNA plasmid that has been genetically engineered to produce one or more specific polypeptide against which an adaptive immune response may be directed.
Vaccines are a well known type of immunogenic composition and typically contain an antigen, such as a microbial or tumour component against which a specific adaptive immune response is to be directed, and an adjuvant, which mimics a cause of ‘danger’ and stimulates an appropriate type of adaptive response to be generated.
A series of compounds known collectively to immunologists as ‘alums’ is known for use as an immune modulator by acting as an adjuvant, which normally stimulates an immune response. The term ‘alum’ is used very generically, and seems to refer to either boehmite (AlOOH) or amorphous aluminum hydroxyphosphate. It should be noted that the ‘alum’ of immunologists is very different to that of the physical sciences; when chemists speak of ‘alum’ they refer to a set of compounds with the formula AB(SO4)2.12H2O, such as KAl(SO4)2.12H2O. Henceforth, the term ‘alum’ should be taken to mean the alum of immunologists.
Alum may act as an adjuvant, to stimulate a certain type(s) of immune response. In so doing, it may lead to modulation or suppression of other types of immune response. Alum is the most widely used adjuvant in human vaccines, but the exact mechanism of action remains unknown. Alum is known to have a good effect in terms of inducing antibody responses (B cell responses) but it does not appear to induce significant generation of cytotoxic T cells. This limits its efficacy in applications such as anti-viral and anti-tumour treatments. Further, the exact chemical structure of alum is not well characterised; it would be preferable to use a chemical product that had a clear and well defined structure, chemical composition, and purity.
There is therefore a need for an improved immune modulator, which can act either as an adjuvant or, in other circumstances, as an immune suppressant.
Layered double hydroxides (LDHs) are a class of compounds that comprise two or more metal cations and have a layered structure. LDHs can be represented by the general formulae (1), or (2) or (3):[MIMIII2(OH)6][An-1/n].zH2O  (1)[MII(1-x)MIIIx(OH)2]x+[An-x/n].zH2O  (2)[MIIMIII4(OH)12][An-2/n].zH2O  (3)wherein: MI, MII and MIII are mono, di- and trivalent metal cations respectively (for example, MI may be Li−, MII may be Ca2+, Mg2+, Ba2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+ Zn2+, or Cd2+, and MIII may be Al3−, Fe3+, Cr3+ V3+ or Co3+), which cations occupy octahedral positions in hydroxide layers;    An- is an interlayer charge-compensating anion with a charge of n (where n is an integer, e.g. 1 or 2), and may be inorganic or organic; examples of A are CO32−, HCO3−, NO3−, Cl−, Br−, SO42−, F− or Br−;    x is a number less than 1; and    z is 0, or a number greater than 0, e.g. from 0.1 to 5, such as from 0.5 to 4.
The values of x have been reported to be from 1/10 to ½. However pure phases only exist for values from ⅕ to ⅓; outside this range compounds with different structures are obtained. It has been proposed that for Mg—Al LDHs with high values of x, Al(OH)3 is formed concomitantly with the LDH, due to the increased number of aluminum octahedra (Am. Mineral, 1979, 64, 836).
Therefore, as the skilled reader will appreciate, MII to MIII in ratios of 1:1 (x=½) would not give rise to a pure LDH product and significant aluminum hydroxide impurities would be present.
A large number of LDHs with a variety of MII-MIII cation pairs (e.g. Ca—Al) have been reported and studied. Furthermore, it is possible to have LDHs in which there is more than one type of MII and/or more than one type of MIII metal ion present. Equally, LDHs having the MI-MIII cation pair Li−Al with different anions in the interlayer space have been reported and studied. A review of LDHs is provided in J. Mater. Chem., 2002, 12, 3191-3198.
It has previously been identified that the surface acidity of LDHs is largely affected by the nature of the interlayer anion (J. Mater. Chem., 1998, 8, 1917-1925). This acidity can be measured using Hammett indicators. The order of acidity of Li—Al and Mg—Al based LDHs has been shown to vary with the nature of the anion, such that carbonate<nitrate<chloride in terms of acidity. The Li—Al and Mg—Al LDHs intercalated with chloride and nitrate exhibited pKa values in the region of 0.1 up to 5.2, whilst those intercalated with carbonate had pKa values above 12.2. Thus anions which are the conjugate bases of weaker acids provide LDHs that are more basic.
Carbonate intercalated LDHs have generally been found to contain basic sites with pKa values in the range of 10.7 to 13.3 and a few sites with a pKa of 16.5 (J. Catal., 1992, 134, 58).